The pathogenesis of Alzheimer's disease (AD), the leading cause of dementia, is not completely understood. As a result, current AD therapies are minimally effective. Unraveling the molecular mechanisms underlying neuronal deficits and assessing the therapeutic value of new drug targets could change this situation. One such target may be phospholipase A2 (PLA2), which releases arachidonic acid (AA), a bioactive lipid, from membrane phospholipids. To assess this possibility, I propose to study transgenic mice expressing mutant human amyloid precursor proteins (hAPP) that, in humans, are linked to familial AD (hAPPFAD mice). hAPPFAD mice develop age-dependent deficits in learning and memory, as well as typical neuropathological hallmarks of AD, including neuritic plaques and gliosis. The functional neuronal deficits in these mice are associated with the brain region-specific depletion of factors involved in synaptic plasticity. AA and its metabolites might promote the accumulation of pathogenic A-beta peptides in the brain, mediate neuroinflammation, and contribute to neurodegeneration and oxidative stress. I will test whether inhibition of PLA2 will prevent and reverse AD-like morphological, molecular, and functional alterations in hAPP mice. [unreadable] [unreadable] [unreadable]